Ferritinophagy Rewires Carnitine‐Dependent Lipid Metabolism to Inhibit PRRSV and IAV Replication

Ferritinophagy is crucial for maintaining iron homeostasis and regulating iron-dependent viral replication. This study demonstrates that ferritinophagy reprograms carnitine-dependent lipid metabolism by impairing Fe-S clusters biogenesis, thereby inhibiting iron-dependent viral replication. Specifically, NCOA4-mediated ferritinophagy disrupts Fe-S clusters assembly through the autophagic degradation of MMS19, leading to mitochondrial metabolic remodeling and suppression of carnitine biosynthesis. Carnitine deficiency subsequently destabilizes the proteins TMED10, HDLBP, and RAB40C via specific amino acid residues (Asp78, Leu336, and Glu154, respectively), and we reveal that carnitine directly stabilizes these lipid droplet-associated proteins, promoting lipid droplet formation. Collectively, these changes orchestrate an iron-lipid metabolic axis that inhibits the replication of diverse PRRSV strains as well as influenza A virus (IAV). Conversely, PRRSV counteracts this antiviral mechanism by promoting autophagic degradation of NCOA4 via K63-linked ubiquitination, a process in which the viral protein Nsp5 recruits the E3 ligase adaptor DDB1 to mediate ubiquitination. Our findings establish NCOA4 as a link between ferritinophagy and lipid metabolic reprogramming, revealing a novel antiviral pathway and providing foundational insights for developing innovative antiviral strategies.